6-chloro-3-cycloalkyl-7-sulfamyl-1,2,4-benzothiadiazine-1,1-dioxides



known to organic chemists.

This invention relates to novel compounds corresponding to the formulaand their non-toxic alkali metal salts. in this and succeeding formulas,R represents cyclopropyl, cyclobutyl, methylcyclopropyl ormethylcyclobutyl. These compounds are crystalline solids soluble in manyorganic solvents but only sparingly soluble in water. They are usefuldiuretic agents when administered orally or by injection, alone or incombination with conventional pharmaceutical carriers as in the formof atablet or a sterile solution. The compounds are readily converted totheir alkali metal salts by reaction with an aqueous or alcoholicsolution of an alkali metal hydroxide such as sodium,

potassiumor lithium hydroxide. If desired, the alkali metal salt may beisolated by evaporating the solvent.

d S tes Patent.

- The new compounds may be prepared by methods well In one such method,5- chloroaniline-2,4-disulfonyl chloride is reacted with acycloalkylcarbonyl chloride of the formula The reaction is preferablycarried in the presence of an inert organic solvent such as benzene orcarbon tetrachloride. Alternatively, the reaction may be carried isadded portionwise to a stoichiometric excess of liquid ammonia at roomtemperature. The resulting solution is thereafter evaporated and anaqueous solution of a mineral acid such as sulfuric acid added to theresidue until the mixture is strongly acidic. The N-cycloalkylcarbonyl-5-chloro-2,4-disulfamylaniline which precipitates as a crystalline solidis separated and recrystallized from a suitable solvent such as amixture of ethyl alcohol and Water.

'ice

In the final step of the method, the disulfamylaniline intermediatehaving the formula is heated preferably at a temperature of about 200 C.for a period of about 2 hours to split off water and effect closure ofthe ring to obtain the desired6-chloro-3-cycloalkyl-7-sulfamyl-l,2,4-benzothiadiazine-1,1-dioxide as acrystalline solid which is separated and purified by recrystallization.

The examples which follow illustrate the invention in detail but are notto be considered as limiting the same to the particular compoundsprepared or the methods specifically employed.

EXAMPLE 1 6-chZora-3-cycl0pr0pyl-7-sulfamyl-1,2,4-benzothiadiazine-1,1-di0xide and sodium salt thereof HzNSO To a solution of 48.7 grams(0.15 mole) of S-chloroaniline-2,4-disulfonyl chloride dissolved in ml.of dry benzene was added portionwise with stirring 31.4 grams (0.3 mole)of cyclopropanecarbonyl chloride. The resulting mixture was refluxed for2 hours and thereafter allowed to stand overnight at room temperature.Upon the addition of pcntane, the desired N-cyclopropanecarbonyl 5chloroaniline-2,4-disulfonyl chloride intermediate precipitated as acrystalline solid. After recrystallization from a benzene-pentanemixture, this compound melted at 122-'123 C. and had the followinganalysis. Calculated for C' H Cl NO S C=30.59%; H 2.05%; Cl 2 7.0-9%.Found: C 31.09%; H=2.53%; Cl= 26.4l%.

45.2 grams (Oill mole) of N-cyclopropanecarbonyI-S-chloroaniline-2,4-disulfonyl chloride was added portionwise to 200 ml.of aqueous ammonia. The resulting solution was evaporated at roomtemperature and 100 ml. of water thereafter added to the viscousresidue. Upon the addition of sulfuric acid, the desiredN-cyclopropanecarbonyl 5 chloro 2,4 disulfamylaniline precipitated.After recrystallization from an ethyl alcohol-water mixture, thiscompound melted at 312-3l4 C. with decomposition and analyzed asfollows. Calculated for C H ClN O S C=33.95%; H=3.42%; N=l1.88%. Found:C=33.97%; H=3.46%; N=l1.70%.

21.2 grams (0.06 mole) of theN-cyclopropanecarbonyl-5-chloro-2,4-disulfamylaniline prepared above washeated on an oil bath at 200 C. for 3 hours. The resulting product wasthen recrystallized from a dimethylformamide-water mixture to obtain6-chloro-3-cyclopropyl-7-sulfamyl-l,2,4-benzothiadiazine-1,l-dioxide asa crystalline solid melting at 326-327 C. with decomposition and havingthe following analysis. Calculated for C H ClN O S C=35.77%; -H=3.00%;N=12.51%; C1 10.56%; S 19.10%. Found: C 35.84%; H=3.l9%; N=12.77%;Cl=10.88%; S=19.07%.

The 6-chloro-3-cyclopropyl-7-sulfamyl-1,2,4-benzothiadiazine-Ll-dioxideobtained above is dissolved in alcoholic sodium hydroxide and thesolvent evaporated under vacuum to yield the corresponding sodium salt.

3 EXAMPLE 2 6-chl0r03-cycl0butyl-7-su'lfamyl-1,2,4-benz0thiadiazine-Ll-dioxide .ILTH (uni-on,

A mixture of 22.7 grams (0.07 mole) of -chloroaniline-2,4-disulfonylchloride and 16.7 grams (0.14 mole) of cyclobutanecarbonyl chloride washeated on the HQNSOZ steam bath until a clear solution was obtained.Upon standing overnight at room temperature, N-cyclobutane-'carbonyl-5-chloroaniline-2,4-disulfonyl chloride precipitated as acrystalline solid which after recrystallization from a benZene-pentanemixture melted at 114-115 C.

and analyzed as follows. Calculated for C H Cl NO S C 32.51%; H 2.48%; O19.69%. Found: C=32.33%; H=2.77%; O=20.02%.

In the second step of the reaction, 22.2 grams (0.05 mole) of thedisulfonyl chloride product prepared above was added portionwise withstirring to 125 ml. of aqueous ammonia. The resulting solution wasevaporated at room temperature and 100 ml. of water thereafter added tothe viscous residue. Upon the addition of concentrated hydrochloric acidto the aqueous solution, N-cyclobutyl'carbonyl-S-chloro-2,4-disulfamylaniline precipitated and was separatedby filtration.

In the third step of the reaction, the disulfamylaniline intermediatewas heated on an oil bath at 200 C. for 3 hours to split on water andclose the ring. There was thus obtained a6-chloro-3-cyclobutyl-7-sulfamyl-1,2,4-

.benzothiadiazine-l,l-dioxide product as a crystalline solid which afterrecrystallization from an ethanol-water mixture was found to melt at362364 C. with decomposition. Analysis.Calculated for C H CIN O SC=37.77%; H=3.46%; N=12.01%; Cl==10.14%; 0:: 18.30%. Found: C 38.31%; H3.89%; N-=ll.54%; Cl=10.-47%;O=18.39%.

EXAMPLE 3 6-chlor0-3-(2'-methylcyclopropyl) -7-sulfamyl-I,2,4-benzothiudiazine-l ,1 -di0xide Z-methylcyclopropanecarbonyl chloride(13.0 grams, 0.11 mole) was added slowly with stirring to a solution of32.5 grams (0.1 mole) of 5-chloroaniline-2,4-disulfonyl chloride in 100ml. of dry benzene and the resulting mixture heated on the steam bathfor 30 minutes. action mixture was allowed to stand overnight at roomThe remediate was thereafter added portionwise to 125 ml. of aqueousammonia and the resulting solution evaporated at room temperature. Aboutml. of water was then added to the viscous, residue followed by thedropwisc addition of concentrated sulfuric acid to precipitate N- (2'methylcyclopropanecarbonyl) 5 chloro 2,4 disulfamylaniline as acrystalline solid which after recrystallization from an ethanol-watermixture melts at 344-345 C. with decomposition. Analysis.--Calculatedfor C I-1 0111 0 5 C=.35.91%; H: 3.84%; N 11.42%. Found: C 36.50%; H3.96%; N=11.87%.

in the final step of the method, 1.7 grams (0.005 mole) of thedisulfamylaniiine product prepared above was heated on a steam bath for2 hours at 200 C. to obtain the desired6-chloro-3-(2'-methylcyclopropyl)-7-sulfamyll,2,4-benzothiadiazine-l,l-dioxideas a crystalline solid which after recrystallization from methanol-watermelted at 344-345 C. Analysis.-Calculated for C I-I CIN O S C=37.77%;H=3.46%; N=12.01%; O: 18.30%. Found: C=38.16%; H=3.51%; N:l1.64%;O=l8.32%.

In a manner similar to that described in the preceding examples, 6chloro-.3-(2'-methylcyclobutyl)-7-sulfamyl-1,2,4-benzothiadiazine-,1,1-dioxide can be prepared by the reaction of5-chloroani1ine-2,4-.disulfonyl chloride with Zmethylcyclobutanecarbonyl chloride, subsequent reaction of theN-(2-methylcyclobutanecarbonyl)5-chloroaniline-2,4-disulfonyl chloridethus formed with annnonia to yield.N-(2'-methylcyclobutanecarbonyl)-5-chloro-2,4- disulfamylaniline andheating the latter compound at about 200 C. to effect ring closure.Reaction of. the dioxide compound with alcoholic potassium hydroxidewill produce the corresponding potassium salt.

This application is a-continuation of our copending application, UsS.Serial .No. 777,212, filed December 1, 1958, now abandoned.

We claim:

1. A compound selected from the class consisting of compoundscorresponding to the formula References Cited in the file of this patentUNITED STATES PATENTS Novello Oct. 8, 1957 OTHER REFERENCES Fieser etal.: Organic Chemistry, pp. 49-50 (D. C. Heath and (30., Boston, 2nded., 1950).

1. A COMPOUND SELECTED FROM THE CLASS CONSISTING OF COMPOUNDSCORRESPONDING TO THE FORMULA